The DOI matches its Crossref record; 5 of the 5 references it cites were found in a registry or an index.
Diabetic Downregulation of Nrf2 Activity via ERK Contributes to Oxidative Stress–Induced Insulin Resistance in Cardiac Cells In Vitro and In Vivo
Open accessAbstract
OBJECTIVE: Oxidative stress is implicated in cardiac insulin resistance, a critical risk factor for cardiac failure, but the direct evidence remains missing. This study explored a causal link between oxidative stress and insulin resistance with a focus on a regulatory role of redox sensitive transcription factor NF-E2–related factor 2 (Nrf2) in the cardiac cells in vitro and in vivo. RESEARCH DESIGN AND METHODS: Chronic treatment of HL-1 adult cardiomyocyte with hydrogen peroxide led to insulin resistance, reflected by a significant suppression of the insulin-induced glucose uptake. This was associated with an exaggerated phosphorylation of extracellular signal–related kinase (ERK). Although U0126, an ERK inhibitor, enhanced insulin sensitivity and attenuated oxidative stress–induced insulin resistance, LY294002, an inhibitor of phosphoinositide 3-kinase (PI3K), worsened the insulin resistance. Moreover, insulin increased Nrf2 transcriptional activity, which was blocked by LY294002 but enhanced by U0126. Forced activation of Nrf2 by adenoviral over-expression of Nrf2 inhibited the increased ERK activity and recovered the blunted insulin sensitivity on glucose uptake in cardiomyocytes that were chronically treated with H2O2. In the hearts of streptozotocin-induced diabetic mice and diabetic patients Nrf2 expression significantly decreased along with significant increases in 3-nitrotyrosine accumulation and ERK phosphorylation, whereas these pathogenic changes were not observed in the heart of diabetic mice with cardiac-specific overexpression of a potent antioxidant metallothionein. Upregulation of Nrf2 by its activator, Dh404, in cardiomyocytes in vitro and in vivo prevented hydrogen peroxide– and diabetes-induced ERK activation and insulin-signaling downregulation. CONCLUSIONS: ERK-mediated suppression of Nrf2 activity leads to the oxidative stress–induced insulin resistance in adult cardiomyocytes and downregulated glucose utilization in the diabetic heart.
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Cites
Reactive oxygen species have a causal role in multiple forms of insulin resistance
Houstis, N., Rosen, E. D., & Lander, E. S. (2006) · Nature · doi:10.1038/nature04634 · Cited by 2,525 · cited 2×
“Oxidative stress is causative of insulin resistance in various cell types (2,6,7,18), which was confirmed by our present study using HL-1 adult cardiomyocytes treated with H2O2.”
BackgroundClaycomb, W. C., Lanson, N. A., Stallworth, B. S., Egeland, D. B., Delcarpio, J. B., Bahinski, A., & Izzo, N. J. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.6.2979 · Cited by 1,546
Doehner, W., Rauchhaus, M., Ponikowski, P., Godsland, I. F., von Haehling, S., Okonko, D. O., Leyva, F., Proudler, A. J., Coats, A. J. S., & Anker, S. D. (2005) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2005.02.093 · Cited by 294
Role of insulin-induced reactive oxygen species in the insulin signaling pathway
Goldstein, B. J., Mahadev, K., Wu, X., Zhu, L., & Motoshima, H. (2005) · Antioxidants & Redox Signaling · doi:10.1089/ars.2005.7.1021 · Cited by 238
Ichikawa, T., Li, J., Meyer, C. J., Janicki, J. S., Hannink, M., & Cui, T. (2009) · PLoS ONE · doi:10.1371/journal.pone.0008391 · Cited by 99
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Cited by
Mechanisms of Diabetic Complications
Forbes, J. M., & Cooper, M. E. (2013) · Physiological Reviews · doi:10.1152/physrev.00045.2011 · Cited by 2,890
Tan, Y., Zhang, Z., Zheng, C., Wintergerst, K. A., Keller, B. B., & Cai, L. (2020) · Nature Reviews Cardiology · doi:10.1038/s41569-020-0339-2 · Cited by 835
Self-citationTherapeutic Potential of Nrf2 Activators in Streptozotocin-Induced Diabetic Nephropathy
Zheng, H., Whitman, S. A., Wu, W., Wondrak, G. T., Wong, P. K., Fang, D., & Zhang, D. D. (2011) · Diabetes · doi:10.2337/db11-0807 · Cited by 507
The Role of Nrf2 in Cardiovascular Function and Disease
Satta, S., Mahmoud, A. M., Wilkinson, F. L., Yvonne Alexander, M., & White, S. J. (2017) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2017/9237263 · Cited by 293
Bai, Y., Cui, W., Xin, Y., Miao, X., Barati, M. T., Zhang, C., Chen, Q., Tan, Y., Cui, T., Zheng, Y., et al. (2013) · Journal of Molecular and Cellular Cardiology · doi:10.1016/j.yjmcc.2013.01.008 · Cited by 274
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Metadata
- Authors
- Tan, Y., Ichikawa, T., Li, J., Si, Q., Yang, H., Chen, X., Goldblatt, C. S., Meyer, C. J., Li, X., Cai, L., & Cui, T.
- Venue
- Diabetes
- Publisher
- American Diabetes Association
- Published
- 2011-01-21
- Volume
- 60
- Issue
- 2
- Pages
- 625-633
- ISSN
- 0012-1797 (ISSN-L)
- 1939-327X
- OpenAlex
- W2123201941
- Cited by
- 392
- References
- 5
- FWCI
- 9.29
- Type
- journal article
- Language
- en
- Open access
- hybrid
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- Tan, Y., Ichikawa, T., Li, J., Si, Q., Yang, H., Chen, X., Goldblatt, C. S., Meyer, C. J., Li, X., Cai, L., & Cui, T. (2011). Diabetic Downregulation of Nrf2 Activity via ERK Contributes to Oxidative Stress–Induced Insulin Resistance in Cardiac Cells In Vitro and In Vivo. Diabetes. https://doi.org/10.2337/db10-1164
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